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Updated: Aug 19, 2025
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma
Staci L Haney1, Dan Feng1, Yashpal S Chhonker2
1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Abstract:
Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.
Insights
Geranylgeranyl diphosphate synthase inhibitors (GGSI) disrupt Rab protein prenylation, triggering cancer cell death and slowing tumor growth. This novel approach shows promise for treating aggressive bone cancers like osteosarcoma and Ewing sarcoma.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Rab GTPases regulate cellular protein trafficking via geranylgeranylation.
- Geranylgeranyl diphosphate synthase (GGDPS) produces the necessary isoprenoid donor (GGPP).
- Targeting Rab activity offers a novel strategy for cancer therapy.
Purpose of the Study:
- To investigate the therapeutic potential of GGDPS inhibitors (GGSI) against osteosarcoma (OS) and Ewing sarcoma (ES).
- To elucidate the molecular mechanisms underlying GGSI-induced cancer cell death.
Main Methods:
- Treatment of OS and ES cell lines with GGSI.
- Assessment of unfolded protein response (UPR) markers and apoptosis.
- Analysis of GGPP levels and Rab geranylgeranylation.
- In vitro migration and invasion assays.
- Metabolomic profiling.
- In vivo tumor growth studies in a mouse model.
Main Results:
- GGSI treatment induced UPR markers and apoptosis in OS and ES cells.
- Effects were confirmed to be due to GGPP depletion and disrupted Rab geranylgeranylation.
- GGSI treatment inhibited cellular migration and invasion.
- Distinct changes in purine metabolism were observed.
- GGSI treatment reduced tumor growth in vivo.
Conclusions:
- GGSI are effective inducers of apoptosis and inhibitors of growth in OS and ES cells.
- GGSI disrupt essential Rab protein prenylation pathways.
- GGSI demonstrate therapeutic potential as a novel treatment for OS and ES.
